Glucocorticoid-induced apoptosis requires FOXO3A activity.
Dexamethasone (DEX) induces apoptosis in lymphocytes, while protecting some cancer cells from apoptosis, by a poorly understood mechanism. In this study, we examined the potential role of the forkhead transcription factor (FOXO3A) in DEX-induced apoptosis. Unphosphorylated FOXO3A, the active form of FOXO3A, can translocate into nucleus and induce apoptosis. In lymphocytes, FOXO3A is upregulated by DEX treatment, while phospho-FOXO3A was downregulated. In several different types of cancer cells, we found that sensitivity to DEX correlated negatively to expression of phospho-FOXO3A. We conclude that DEX might maintain FOXO3A in its unphosphorylated, active form. Knockdown of FOXO3A expression using a small interfering RNA (siRNA) significantly reduces apoptosis in lymphocytes. This study suggests that FOXO3A has a pivotal role in DEX-induced apoptosis. Increased phospho-FOXO3A levels in cancer cells may explain, in part, their resistance to apoptosis. Therefore, FOXO3A may be a potential target for cancer therapy.
Ma
Jiexian
J
The Hematology Department of Huashan Hospital Affiliated in Fudan University, Shanghai 200040, China.
Xie
Yanhui
Y
Shi
Yi
Y
Qin
Wenming
W
Zhao
Botao
B
Jin
Youxin
Y
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D005938:Glucocorticoids; D034741:RNA, Small Interfering; D003907:Dexamethasone